Metformin potentiates the anticancer effects of cisplatin under normoxic conditions in vitro

Abstract

Metformin is a diabetes drug with anticancer properties. Several studies have investigated the effects of metformin combined with chemotherapeutic agents, with controversial results. This study evaluated the efficacy of combined metformin/cisplatin treatment in an endometrial cancer cell line. Ishikawa cells were treated with metformin, cisplatin or both types of treatment. Cell proliferation was evaluated by quantification and colorimetric and thymidine incorporation assays, cell cycle progression was assessed by flow cytometry, and apoptosis by the caspase-3 activity assay. The effects of metformin and cisplatin used in combination were assessed under normoxic (21% O2) and hypoxic (1% O2) conditions. Mitochondrial morphology was examined using the MitoTracker dye, while function was assayed by lactate production. Discrepant results were obtained from the different assays of cell proliferation, with the value obtained from the colorimetric assay being higher than that from cell counts after drug treatment. Combined treatment with metformin (≥2 mM) and cisplatin (1 µM) had additive anti-proliferative effects on cells under normoxic conditions. However, the additive effect of metformin was attenuated under hypoxia. Metformin caused morphological and functional changes in mitochondria, which appeared shortened after exposure to metformin, while the connections between individual mitochondria appeared weaker. Additionally, decreased MitoTracker staining was observed after an 8-h exposure to metformin. The colorimetric assay did not accurately determine the effects of metformin and cisplatin on cell proliferation. The additive effects of metformin on cisplatin-induced inhibition of cell proliferation were attenuated under hypoxic conditions, while metformin compromised mitochondrial structure and function. Additional studies are needed to determine the efficacy of this drug combination in vivo.

Metformin Increases E-cadherin in Tumors of Diabetic Patients With Endometrial Cancer and Suppresses Epithelial-Mesenchymal Transition in Endometrial Cancer Cell Lines

“…38,39 Different sublines of Ishikawa cells used in different laboratories, different viability assays, and different cell culture media may explain the dissimilar sensitivity of these cells as found in the different literature reports. In addition, we observed the inhibitory effect of metformin on cell migration in a time-and concentration-dependent manner and at lower than 1-mM dose of metformin, in support of our conclusion that the inhibitory effect of metformin on cell migration is genuine and is not due to cell death.…”

Metformin as a Therapeutic Target in Endometrial Cancers

“…Metformin has demonstrated the ability to synergize with other endometrial cancer therapies in vitro , leading to enhanced apoptosis of cultured endometrial cell lines in the presence of paclitaxel (74, 101), cisplatin (101, 102), or progestin (89). For the latter two, this effect is dependent on downregulation of glycoxylase I (GloI), a mediator of chemotherapy resistance (89, 101).…”

Metformin as target metabolic drug in oncology

“…Напоминаем, что мет-формин -это метилирующий агент, а из эпидемиоло-гических исследований [25] установлено, что при ста-рении происходят широкомасштабные изменения профилей метилирования. Обычно наибольшее коли-чество метилированных цитозиновых оснований на-блюдается в ДНК, выделенной из эмбрионов или но-ворождённых животных, и это количество постепенно уменьшается с возрастом.…”

“…Исследователи Уиттерского колледжа, изучающие рак, предлагают свою версию возможного механизма цито-токсического влияния метформина на злокачественные опухоли [25]. Согласно этой версии, во первых, назначение метформина приводит к дефициту и фолатов, и витами-на В 12 (в сыворотке крови меньше 150 пМ) у 30 % больных СД.…”

“…В гипоксических условиях метформин в комбинации с цисплатином оказывает антипролиферативный эффект и приводит как к структурным, так и функциональным из-менениям в митохондриях [25].…”